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Sepsis lethality via exacerbated tissue infiltration and TLR-induced cytokine production by neutrophils is integrin α3β1-dependent

Authors
 Yelena V. Lerman  ;  Kihong Lim  ;  Young-Min Hyun  ;  Kathleen L. Falkner  ;  Hongmei Yang  ;  Anthony P. Pietropaoli  ;  Arnoud Sonnenberg  ;  Pranita P. Sarangi  ;  Minsoo Kim 
Citation
 Blood, Vol.124(24) : 3515-3523, 2014 
Journal Title
 Blood 
ISSN
 0006-4971 
Issue Date
2014
MeSH
Animals ; Cytokines/genetics ; Cytokines/immunology* ; Disease Models, Animal ; Humans ; Integrin alpha3beta1/antagonists & inhibitors ; Integrin alpha3beta1/genetics ; Integrin alpha3beta1/immunology* ; Male ; Mice ; Mice, Knockout ; Neutrophil Infiltration/drug effects ; Neutrophil Infiltration/genetics ; Neutrophil Infiltration/immunology* ; Neutrophils/immunology* ; Neutrophils/pathology ; Peptides/pharmacology ; Sepsis/chemically induced ; Sepsis/drug therapy ; Sepsis/genetics ; Sepsis/immunology* ; Sepsis/pathology ; Toll-Like Receptors/genetics ; Toll-Like Receptors/immunology*
Abstract
Integrin-mediated migration of neutrophils to infected tissue sites is vital for pathogen clearance and therefore host survival. Although β2 integrins have been shown to mediate neutrophil transendothelial migration during systemic and local inflammation, relatively little information is available regarding neutrophil migration in sepsis beyond the endothelial cell layer. In this study, we report that integrin α3β1 (VLA-3; CD49c/CD29) is dramatically upregulated on neutrophils isolated from both human septic patients and in mouse models of sepsis. Compared with the α3β1 (low) granulocytes, α3β1 (high) cells from septic animals displayed hyperinflammatory phenotypes. Administration of a α3β1 blocking peptide and conditional deletion of α3 in granulocytes significantly reduced the number of extravasating neutrophils and improved survival in septic mice. In addition, expression of α3β1 on neutrophils was associated with Toll-like receptor-induced inflammatory responses and cytokine productions. Thus, our results show that α3β1 is a novel marker of tissue homing and hyperresponsive neutrophil subtypes in sepsis, and blocking of α3β1 may represent a new therapeutic approach in sepsis treatment.
Full Text
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4256905/
DOI
10.1182/blood-2014-01-552943
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
Yonsei Authors
현영민(Hyun, Young-Min) ORCID logo https://orcid.org/0000-0002-0567-2039
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/158596
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